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Cited by 16Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

Excessive/Aberrant and Maladaptive Synaptic Plasticity: A Hypothesis for the Pathogenesis of Alzheimer’s Disease

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Kawabata, Shigeki·2022·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2022.913693PMC PMC9294348
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Abstract

The amyloid hypothesis for the pathogenesis of Alzheimer’s disease (AD) is widely accepted. Last year, the US Food and Drug Administration considered amyloid-β peptide (Aβ) as a surrogate biomarker and approved an anti-Aβ antibody, aducanumab, although its effectiveness in slowing the progression of AD is still uncertain. This approval has caused a great deal of controversy. Opinions are divided about whether there is enough evidence to definitely consider Aβ as a causative substance of AD. To develop this discussion constructively and to discover the most suitable therapeutic interventions in the end, an alternative persuasive hypothesis needs to emerge to better explain the facts. In this paper, I propose a hypothesis that excessive/aberrant and maladaptive synaptic plasticity is the pathophysiological basis for AD.

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  • According to the maladaptive synaptoplasticity hypothesis, amyloid plaques, tau pathology, and synaptic loss are not independent triggers but downstream consequences of aberrant plasticity driven by genetic and environmental risk factors.

    “According to this view, the hallmark features of AD, amyloid plaques, tau pathology, and synaptic loss are not independent triggers, but rather downstream consequences of aberrant plasticity driven by genetic and environmental risk factors [80, 81].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [81]

    The Conclusion (page unavailable) proposes aberrant synaptic plasticity as a cause of AD and describes amyloid plaques and neurofibrillary tangles as possible byproducts. It also links APP and presenilin mutations, and the APOE ε4 risk factor, to aberrant or excessive plasticity. The copy reports later synapse loss in AD mice, but does not clearly identify synaptic loss as a byproduct of plasticity or establish the claimed role for environmental risk factors. (LLM, conf=0.83)

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  • The maladaptive synaptoplasticity hypothesis proposes that the initiating event in AD is an abnormal synaptic plasticity response, whereby excessive or dysfunctional remodeling in evolutionarily vulnerable postsynaptic neurons drives the cascade of pathological changes.

    “The maladaptive synaptoplasticity hypothesis proposes that the initiating event in AD is an abnormal synaptic plasticity response, whereby excessive or dysfunctional remodeling in evolutionarily vulnerable postsynaptic neurons drives the cascade of pathological changes [80, 81].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [81]

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  • A reduction in presynaptic input initiates maladaptive responses that ultimately promote the formation of NFTs.

    “Specifically, a reduction in presynaptic input initiates maladaptive responses that ultimately promote the formation of NFTs.”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [81]

    The Conclusion proposes that NFTs may be byproducts of excessive or aberrant synaptic plasticity. The Mechanism of Network Abnormalities describes reduced synapses at a site of entorhinal input alongside possible compensatory reweighting, but does not establish reduced presynaptic input as the initiator of a pathway to NFTs. The citing sentence also states as fact a connection the paper presents as a hypothesis. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Kawabata, S.
Corresponding author
Kawabata, Shigeki
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2022-07-05
Volume
14
Pages
913693-913693
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2022.913693
PMC
PMC9294348
OpenAlex
W4283806926
Cited by
16
References
9
Citations by year
2026: 3 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 3
FWCI
1.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Johns Hopkins University
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Alzheimer's disease pathogenesis, synaptic plasticity, amyloid hypothesis, amyloid-beta, aducanumab, anti-amyloid antibodies, alternative hypothesis

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